US5556941A - Glycopeptide derivatives, a process for their preparation and pharmaceutical agents containing these compounds - Google Patents

Glycopeptide derivatives, a process for their preparation and pharmaceutical agents containing these compounds Download PDF

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US5556941A
US5556941A US08/291,729 US29172994A US5556941A US 5556941 A US5556941 A US 5556941A US 29172994 A US29172994 A US 29172994A US 5556941 A US5556941 A US 5556941A
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alkyloxy
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methanol
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Cenek Kolar
Werner Stuber
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Siemens Healthcare Diagnostics GmbH Germany
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Behringwerke AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K9/00—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof
    • C07K9/001—Peptides having up to 20 amino acids, containing saccharide radicals and having a fully defined sequence; Derivatives thereof the peptide sequence having less than 12 amino acids and not being part of a ring structure
    • C07K9/003—Peptides being substituted by heterocyclic radicals, e.g. bleomycin, phleomycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention relates to N-glycopeptide derivatives, a process for their preparation and a pharmaceutical agent which contains these novel compounds.
  • the main step in the coagulation of blood involves the conversion of the soluble protein fibrinogen into the insoluble protein fibrin.
  • a proteolytic catalyst for this, thrombin, is necessary.
  • proteolysis By proteolysis the proenzyme prothrombin is converted into thrombin.
  • This proteolysis is set in motion by extravascular or intravascular activation processes.
  • the hemostatic equilibrium is regulated not only by activators but also by inhibitors of both coagulation and fibfinolysis.
  • the most important physiological inhibitor of coagulation is antithrombin III (AT III). It inactivates thrombin only to a minor extent initially and in larger measure only after a certain onset time. AT III thus participates directly in an interception mechanism directed against excessive activation of thrombin.
  • Anticoagulants such as AT III and heparin, and recently hirudin as well, are employed in the therapy of thrombotic disorders, as are coumarin derivatives in prophylaxis. Use of the anticoagulants listed here is associated with disadvantages. Heparin, which is not a single molecule, is only active in the presence of the cofactor AT III. It can only be administered parenterally.
  • Himdin or AT III must be isolated from biological material or prepared by gene technology. Long-term prophylaxis with the coumarins, which are antagonistic to vitamin K, is associated with side effects, such as hemorrhagic skin neeroses, loss of hair and nausea.
  • low molecular weight anticoagulants which act directly on the proteolytically active center of the thrombin, for example serine protease inhibitors, which are derived from a peptide boronic acid. These compounds inhibit not only thrombin but also other serine proteases such as trypsin.
  • NAPAP 2-N-(2-naphthalenesulfonylglycyl)-4-amidino-phenylalaninc piperidide
  • the object of the present invention became to prepare novel N-glycopeptide derivatives with anticoagulant activity. This object was achieved by the preparation of the compounds of the formula I.
  • the invention relates to N-glycopeptide derivatives of the formula I ##STR2## where aromatic is an unsubstituted or substituted benzene residue, naphthalene residue, chroman residue, chromene residue or coumarone residue,
  • a is 0 to 5
  • b is 0 to 4
  • c is 0 or 1
  • d is 1 or 2
  • R 1 is (C 1 -C 3 )-alkyl
  • R 2 is (C 1 -C 3 )-alkyl or (C 1 -C 3 )-alkyloxy
  • R 3 is H, OH, (C 1 -C 3 )-alkyloxy, NH 2 , NH-(C 1 -C 6 )-alkanoyl, NH-benzoyl, NH-SO 3 H or NH-acyl radical of a natural N-acetylated amino acid,
  • R 4 is H, OH, or (C 1 -C 3 )-alkyloxy
  • R 5 is H, OH, (C 1 -C 3 )-alkyloxy, fluorine, chlorine or bromine,
  • R 6 is H, CH 3 , CH 2 OH, CH 2 O --(C 1 -C 6 )-alkanoyl, CH 2 NHCOCH 3 or CH 2 NH-SO 3 H,
  • R 5 and R 6 are together O--CH 2 --O--CH 2 , O-CH(CH 3 )-O-CH 2 or
  • R 7 is hydroxy-(C 2 -C 4 )-alkyl or (C 2 -C 4 )-alkyloxy-(C 2 -C 4 )-alkyl,
  • R 8 is H or (C 1 -C 6 )-alkyl or
  • R7-N-R 8 are together a pyrrolidine ring, piperdine ring or morpholine ring, which can be substituted by HO, HOCH 2 , CH 3 or COOH,
  • W is --O--, --CONH-- or --C 6 H 4 --CONH and
  • H-X is HCl, a (C 1 -C 7 )-alkanoic acid or another pharmacologically tolerated inorganic or organic acid.
  • aromatic is an unsubstituted or substituted benzene residue, naphthalene residue or chroman residue,
  • a is 0 to 4
  • b is 0 to 2
  • c is 0 or 1
  • d is 1 or 2 and
  • R 1 is CH 3 ,
  • R 2 is CH 3 or CH 3 O
  • R 3 is H, OH, (C 1 -C 3 )-alkyloxy, NH 2 , NH-acetyl, NH-benzoyl, NH-SO 3 H or NH-acyl radical of N-acetyl- glycine or N-acetylalanine,
  • R 4 is H or OH
  • R 5 is H or OH
  • R 6 is H, CH 3 , CH 2 OH or CH 2 NH--SO 3 H,
  • R 5 and R 6 are together O--CH 2 --O--CH 2 or O--CH(CH 3 )--O--CH 2 ,
  • R 7 is hydroxypropyl or ethoxypropyl
  • R 8 is H or (C 1 -C 6 )-alkyl or
  • R 7 -N-R 8 are together a pyrrolidine ring, piperidine ringor morpholine ring
  • W is --O--, --CONH-- or --C 6 H 4 --CONH and
  • H-X is HCl, (C 1 -C 6 )-alkanoic acid or another pharmacologically acceptable inorganic or organic acid.
  • the compounds according to the invention of the formula I may be prepared by reacting a compound of the formula II,
  • aromatic is an unsubstituted or substituted benzene residue, naphthalene residue, chroman residue, chromene residue or coumarone residue, a is 0 to 5, b is 0 to 4, and
  • R 1 is (C 1 -C 3 )-alkyl
  • R 2 is (C 1 -C 3 )-alkyl or (C 1 -C 3 )-alkyloxy, with an N-glycoside of the formula III, ##STR3## where c is 0 or 1, d is 1 or 2,
  • R 3 is H, O protective group, where "protective group" within the framework of this invention is a protective group which is customary in carbohydrate chemistry or peptide chemistry, NH protective group, NH--SO 3 H, (C 1 -C 3 )-alkyloxy, NH-(C 1 -C 6 )-alkanoyl, NH-benzoyl, NH--SO 3 H or NH-acyl radical of a natural N-acetylated amino acid,
  • R 4 is H, O protective group or (C 1 -C 3 )-alkyloxy
  • R 5 is H, O protective group, (C 1 -C 3 )-alkyloxy, fluorine, chlorine or bromine,
  • R 6 is H, CH 3 , CH 2 -O protective group, CH 2 O-(C 1 -C 6 )-alkanoyl, CH 2 NHCOCH 3 , CH 2 NH--SO 3 H,
  • R 5 and R 6 are together O--CH 2 --O--CH 2 , O--CH(CH 3 )--O--CH 2 or O--C(CH 3 ) 2 --O--CH 2 and
  • R 9 is a methyl group, tert-butyl group, allyl group or benzyl group and
  • W is --O--, --CONH-- or --C 6 H 4 --CONH
  • a sulfonamide compound of the formula V ##STR4## where a, b, c and d and the residues retain their previously indicated meaning, eliminating the radical R 9 in the product selectively by hydrolysis with HCl acetic acid or trifiuoroacetic acid/water or by hydrogenolysis in the presence of palladium/carbon and a (C 1 -C 4 )-alcohol, acetic acid or ethyl acetate as solvent, and reacting the product obtained, in which R 9 is a hydrogen atom, with a phenylalanine derivative of the formula IV,
  • R 7 is hydroxy-(C 2 -C 4 )-alkyl or (C 2 -C 4 )-alkyloxy-(C 2 -C 4 )-alkyl,
  • R 8 is H or (C 1 -C 6 )-alkyl or
  • R 7 -N-R 8 are together a pyrrolidine ring, piperidine ring or morpholine ring and
  • H-X is HCl, HI or CF 3 COOH, according to a condensation procedure which is customary in peptide chemistry, to form a compound of the formula I, where a, b, c and d and the residues retain their previously indicated meaning, and removing the protective groups in the product according to procedures which are customary in carbohydrate or peptide chemistry, resulting in the formation of a further product of the formula I, where aromatic is an unsubstituted or substituted benzene residue, naphthalene residue, chroman residue, chromene residue or coumarone residue,
  • a is 0 to 5
  • b is 0 to 4
  • c is 0 or 1
  • d is 1 or 2 and
  • R 1 is (C 1 -C 3 )-alkyl
  • R 2 is (C 1 -C 3 )-alkyl or (C 1 -C 3 )-alkyloxy
  • R 3 is H, OH, (C 1 -C 3 )-alkyloxy, NH 2 , NH--(C 1 -C 6 )-alkanoyl, NH-benzoyl, NH--SO 3 H or NH-acyl radical of a natural N-acetylated amino acid,
  • R 4 is H, OH, or (C 1 -C 3 )-alkyloxy
  • R 5 is H, OH, (C 1 -C 3 )-alkyloxy, fluorine, chlorine or bromine,
  • R 6 is H, CH 3 , CH 2 OH, CH 2 O--(C 1 -C 6 )-alkanoyl, CH 2 NHCOCH 3 or CH 2 NH--SO 3 H,
  • R 5 and R 6 are together O--CH 2 --O--CH 2 , O--CH(CH 3 )O--CH 2 or O--C(CH 3 ) 2 --O--CH 2 ,
  • R 7 is hydroxy -(C 2 -C 4 )-alkyl or (C 2 -C 4 )-alkyloxy-(C 2 -C 4 )-alkyl,
  • R 8 is H or (C 1 -C 6 )-alkyl or
  • R 7 -N-R 8 are together a pyrrolidine ring, piperidine ring or morpholine ring,
  • W is --O--, --CONH-- or --C 6 H 4 --CONH and
  • H-X is HCl or (C 1 -C 6 )-alkanoic acid, and optionally converting the glycopeptide derivative thus obtained into another pharmacologically tolerated salt.
  • the condensation by the process according to the invention is carried out by the general methods of peptide chemistry, preferably by the method of mixed anhydrides, by way of active esters, azides, or by the carbodiimide method, in particular with the addition of reaction-accelerating and racemization-inhibiting substances such as, for example, 1-hydroxy-benzotriazole (HOBt), N-hydroxysuccinimide, N-hydroxy-5-norbomene-2,3-dicarboximide, additionally using activated derivatives of 1-hydroxybenzotriazole or anhydrides of phosphoric, phosphonic and phosphinic acids at a reaction temperature between -5° C. and 40° C.
  • reaction-accelerating and racemization-inhibiting substances such as, for example, 1-hydroxy-benzotriazole (HOBt), N-hydroxysuccinimide, N-hydroxy-5-norbomene-2,3-dicarboximide, additionally using activated derivatives of 1-hydroxybenzotriazole or anhydrides of phospho
  • Suitable solvents for this are dimethylformamide (DMF), dimethylacetamide (DMA), hexamethylphosphoric triamide (HMPT), N-methylpyrrolidone or dimethyl sulfoxide (DMSO).
  • solvents such as methylene chloride, chloroform or dichloroethylene may be employed. The indicated methods are described, for example, in Meienhofer-Gross: "The Peptides", Academic Press, vol. I, (1979).
  • protective groups which are customary in carbohydrate or peptide chemistry, for amino groups, hydroxyl groups or carboxyl groups is determined by the synthesis strategy as well as the nature of the coupling conditions.
  • Protective groups which are customary in carbohydrate chemistry for the hydroxyl group are understood as meaning, for example, the (C 1 -C 10 )-acyl protective groups such as (C 1 -C 6 )-alkanoyl (e.g.
  • the amino groups are protected using adamantyloxycarbonyl (Adoc) groups, benzyloxycarbonyl (Z) groups, p-nitrobenzyloxycarbonyl (pNBz) groups, 9-fluorenylmethoxycarbonyl (Fmoc) groups, tert-butyloxycarbonyI (BOC) groups or ⁇ , ⁇ -dimethyl-3,5-dimethoxybenzyloxycarbonyl (DDZ) groups or trifluoroacetyl (TFAc) groups.
  • Adoc adamantyloxycarbonyl
  • Z benzyloxycarbonyl
  • pNBz p-nitrobenzyloxycarbonyl
  • Fmoc 9-fluorenylmethoxycarbonyl
  • BOC tert-butyloxycarbonyI
  • DDZ ⁇ , ⁇ -dimethyl-3,5-dimethoxybenzyloxycarbonyl
  • TFAc trifluoroacetyl
  • the carboxyl groups are protected using (C 1 -C 4 )-alkyl groups, allyl (All) groups or benzyl (Bn) groups.
  • Protective groups can be eliminated by customary methods, in each case according to the nature of the particular group, for example with trifluoroacetic acid, HCl or HBr in acetic acid or by mild reduction, for example with hydrogen and a catalyst, such as palladium/carbon or palladium/barium sulfate in (C 1 -C 4 )-alcohol, acetic acid or ethyl acetate.
  • the Fmoc protective group can be eliminated with piperidine, morpholine or other secondary amines, optionally by catalytic hydrogenation (e.g. R. Geiger and W. Konig in E. Gross and Meienhofer (eds.): The Peptides, vol. 3, p. 24, Academic Press 1981).
  • O-acyl protective groups and COO-alkyl protective groups are advantageously eliminated in a basic environment, for example with sodium methylate, sodium hydroxide, sodium carbonate, barium oxide or potassium cyanide, or with organic bases, such as, for example, hydrazine in (C 1 -C 4 )-alkanol, or their mixtures with chloroform or water.
  • N-glycopeptide building blocks of the formula III two polyfunctional reactants (carbohydrate and amino dicarboxylic acid) have to be linked. It must be possible to block and deblock both of them selectively.
  • N-glycosidic linkage (1,2-cis-N-glycoside or 1,2-trans-N-glycoside) which is being sought, it is necessary to introduce appropriate protective groups for the blocking of the hydroxyl groups, carboxyl groups or amino groups into the glycosyl component as well as the amino acid component, and to work out reaction conditions for the linkage step, which leads stereoselectively to only one of the two possible anomers.
  • N-glycopeptide building blocks of the formula III either the methods known in the literature are used, as described, for example, by A. Y. Khorlin et al. Carbohydr. Res., 85, 201-208 (1980), R. Walczyna and J. Sokolowski, Carbohydr. Res., 180, 147-151 (1988), A. Klemmer and M. Kohla, J. Carbohydr. Chem., 7(4), 785-797 (1988), T. Takeda et al., Carbohydr. Res., 207, 71-79 (1990), W. Guenther and H. Kunz, Angew. Chem., 102/9, 1068 (1990), L.
  • the pharmaceutical applicability of the novel compounds of the formula I as anticoagulants was investigated in various in vitro and in vivo test systems.
  • inhibition constants K i
  • the specificity of the novel compounds towards serine proteases was investigated in particular with thrombin and trypsin.
  • the in vivo activity of the compounds of the formula I was established by determining the acute toxicity (LD 5 , LD 50 ) and partial thromboplastin time (PTT).
  • the chemical stability of the novel compounds with regard to oral administration was ascertained with strong acids and alkalis.
  • the stability of the novel compounds towards degrading enzymes was tested with trypsin and chymotrypsin, as well as indirectly with plasma, and liver or intestinal homogenates.
  • the invention further relates to pharmaceutical formulations which contain a glycopeptide derivative of the formula I and a pharmaceutical diluent, a solubilizing agent or an excipient.
  • An advantageous pharmaceutical formulation is the one in which a compound of the formula I is present in the form of an emulsion or a liposomal or micellar preparation.
  • auxiliary molecules which can be used for producing a pharmaceutically acceptable formulation are phospholipids, cholesterol, triglycerides, and detergents such as, for example, TweenR 80 or their mixtures.
  • Suitable excipients are, for example, albumins, gelatin polymers such as polygeline or starch, glucose, lactose, mannitol or sorbitol, which are present in a physiological solution or solid form. These formulations contain a therapeutically effective quantity of the glycopeptide compound of the formula I.
  • Method B The N-Z-protected compound 5 (0.9 g) was dissolved in ethyl acetate and methanol 1:1 (20 mL) and hydrogenated in the presence of Pd/C (0.4 g). After filtering off the catalyst, the flitrate was concentrated by evaporation, and the product obtained was used in the next reaction without further purification steps. Yield: 0.75 g.
  • N-Z-protected compound 7 (2.2 g) was dissolved in ethyl acetate/methanol 1:1 (50 mL) and hydrogenated in the presence of palladium/carbon (10%: 1.2 g) for 5 h. After filtering off the catalyst, the solution was concentrated in vacuo, and the residue was codistilled twice with toluene. The product obtained (1.32 g) was used without further purification for the following reaction.
  • Compound 27 was deacetylated with barium oxide as described above.
  • Compound 28 was deacetylated with barium oxide as described above.
  • N-(tert.-Butyloxycarbonyl)-D-(p-cyano)phenylalanine 5.0 g was dissolved in DMF (50 mL).
  • the inhibition constants (K i ) of the compounds of the formula I were determined in established enzyme-kinetic procedures.
  • the human thrombin which was employed was determined by active site titration to be 87% pure.
  • the test solution for the Ki determination was composed of buffer (50 mM Tris-HCl, 75 mM NaCl, pH 7.8, 37° C.), 100 pM thrombin, 0.1 nM H-D-phenylalanyl-L-pipecolyl-L-argubube-p-butriabukude dihydrochloride (substrate S-2238; from Kabi) and inhibitor, which embraced a range from 0 to 400 nM.
  • Inhibitor and enzyme were preincubated for 10 minutes, and the reaction was started by addition of the chromogenic substrate S2238.
  • the mathematical algorithm for tight-binding was used, which gave K i values and the inhibition type with the aid of non-linear regression. The inhibition type was found to be competitive for all the inhibitors.
  • the specificity of the inhibitors towards thrombin and trypsin was determined.
  • the K i of trypsin was determined in an analogous manner to the determination of the K i of thrombin.
  • the reaction mixture was composed as follows--buffer: 200 mM triethanolamine, 20 mM CaCl 2 , pH 7.8; 37° C.; enzyme: 0.5 nM trypsin from bovine pancreas; substrate: 500 ⁇ M carbobenzoxy-L-valyl-glycyl-L-arginine-4-nitranilide (Chromozyme TRY, from Boehringer Mannheim).
  • the enzymatic reaction was started after a 10 minute preincubation by addition of the substrate.
  • the p-nitroaniline which was liberated was measured at 405 nm.
  • Table I The results are summarized in Table I.
  • CD rats were injected i.v. on day 0 with different doses of the test substance dissolved in 0.5 mL of physiol. NaCl solution. Control groups received only 0.5 mL of physiol. NaCl solution. 2 rats were used per concentration of the test substance. The number of rats surviving on day 1 was determined and the LD 5 , LD 50 and LD 95 were calculated by the Litchfield & Wilcoxon method. The toxicity, LD 50 (mg/kg), of the compounds described here was determined in comparison with NAPAP. The results are summarized in Table I. Pharmacological data and activities of some selected compounds:
  • Partial thromboplastin time (PTT)-screening test for defects in the intrinsic and extfinsic coagulation system :
  • the compounds to be tested were administered i.v. as a bolus into the tail vein of the rat. After 5 min blood was removed from a venous plexus and mixed with 1/5 the volume of citrate buffer. PTT was determined in a coagulometer (Schnittger & Gross) with neothrombin. The normal PTT values for the rat are in the region of 20 sec. For the determination of thrombin time (TT), 100 ⁇ L of blood, citrate buffer and diethyl barbiturate-acetate buffer were mixed and incubated for 1 min at 37° C. After the addition of 100 ⁇ L of test thrombin, TT was determined in a coagulometer.
  • TT thrombin time
  • Stage 1 Synthesis of 2-N-(4-Methoxy-2,3,6-trimethyl-benzenesulfonyl)-3-O-(2,3,4-tri-O-acetyl-.beta.-D-ribopyranosyl)-L-seryl-4-cyano-D-phenylalanyl-piperdine: 3-0-(2,3,4-tri-O-acetyl- ⁇ -D-fibopyranosyl)-L-serin-tert.-butyl ester (17.3 g), tri-ethylamine (12 mL) and MIr chloride were dissolved in DMF (800 mL) and stirred at room temperature overnight.
  • DMF 800 mL
  • Cyanophenylalanine glycopeptide (10.0 g) was dissolved in dry pyridine (100 mL) and, after addition of triethylamine (2.5 mL), gaseous hydrogen sulfide was passed for 3 h. The mixture was left to stand at room temperature for 3 days and then poured into a mixture of ice (300 g) and concentated HCl. The precipitate was was filtered off with suction and washed with water. The thioamide was dried and then taken up in acetone (200 mL), and methyl iodide (5.0 mL) was added. The mixture was boiled under reflux for 30 minutes. After cooling, precipitation was induced with diethyl ether.
  • Stage 3 Deacylation of 2-N-(4-Methoxy-2,3,6-trimethyl-benzenesulfonyl)-3-O-(2,3,4-tri-O-acetyl-.beta.-D-ribopyranosyl)-L-seryl-4-amidino-D-phenylalanylpiperidine ⁇ HI:
  • N-Benzyloxycarbonyl-4-cyano-D and L-phenylalanine- ⁇ -benzyl ester (5.0 g) was reacted with H 2 S and then with methyl iodide as described in example 15 (stage 2) to give S-methyl-thioimide intermediate (4.2 g).
  • the intermediate was hydrolyzed with aq. 5% KHSO 4 /acetone according to customary method and worked up to give Somethyl-thioester, which was hydrolyzed according to Zemplen method to N-Benzyloxycarbonyl-4-carboxy-phenylalanine- ⁇ -benzyl ester.
  • the intermediate was protected with Fmoc chloride to give the title compound 51 or 52.

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US20040063725A1 (en) * 2001-01-08 2004-04-01 Martine Barth Novel n(phenylsulphonyl)glycine derivatives and their therapeutic use
US20050222140A1 (en) * 2002-07-11 2005-10-06 Colandrea Vincent J Phenylalanine derivatives as depeptidyl peptidase inhibitors for the treatment or prevention of diabetes

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WO1999040063A1 (fr) * 1998-02-06 1999-08-12 Yoshitomi Pharmaceutical Industries, Ltd. Nouveaux derives de l'acide hydroxamique de type azapeptide
US6486129B1 (en) * 1998-06-17 2002-11-26 Akzo Nobel N.V. Antithrombotic compounds
US6723722B1 (en) 1999-06-22 2004-04-20 Takeda Chemical Industries, Ltd. Acylhydrazine derivatives, their production and use
TWI289566B (en) * 1999-12-07 2007-11-11 N.V.Organon Antithrombotic compound
DE10049937A1 (de) * 2000-10-06 2002-04-11 Knoll Ag Niedermolekulare Inhibitoren von Serinproteasen mit Polyhydroxyalkyl- und Polyhydroxycycloalkylresten
FR2840897B1 (fr) 2002-06-14 2004-09-10 Fournier Lab Sa Nouveaux derives d'arylsulfonamides et leur utilisation en therapeutique
EA008921B1 (ru) 2003-03-25 2007-08-31 Лаборатуар Фурнье С.А. Производные бензолсульфонамидов, способ их получения и их применение для лечения боли
US9820986B2 (en) * 2005-03-04 2017-11-21 Taiwan Hopaz Chems, Mfg. Co., Ltd. Glycopeptide compositions

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US20040063725A1 (en) * 2001-01-08 2004-04-01 Martine Barth Novel n(phenylsulphonyl)glycine derivatives and their therapeutic use
US20050222140A1 (en) * 2002-07-11 2005-10-06 Colandrea Vincent J Phenylalanine derivatives as depeptidyl peptidase inhibitors for the treatment or prevention of diabetes
US7157490B2 (en) * 2002-11-07 2007-01-02 Merck & Co., Inc. Phenylalanine derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes

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IL104931A (en) 1996-10-31
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